The present invention relates to a process for the preparation of single phase magnesium- and carbonate-substituted hydroxyapatite compositions which are stable on heating and which do not contain sodium or ammonium ions.
Synthetic hydroxyapatite Ca10(PO4)6(OH)2 has been reported as having been used as a bone replacement material in porous, granular, plasma sprayed and dense forms. Investigations have shown hydroxyapatite to be similar structurally to bone material. However, hydroxyapatite is one of the range of stoichiometric calcium phosphate apatites. Human and animal bone have been shown to contain significant amounts of from 3 to 7 wt % of carbonate. Furthermore, human and animal bone also contains approximately 0.5% by weight of magnesium. There is evidence that the carbonate group can substitute in two sites, the phosphate and hydroxyl sites, termed B and A respectively; bone mineral being predominantly a B type apatite. As a result of this similarity in chemical composition, it is envisaged that a magnesium/carbonate-substituted hydroxyapatite will have better bioactivity than unsubstituted stoichmetric hydroxyapatite which is currently used in commercial applications such as plasma-sprayed coatings on metallic implants and porous hydroxyapatite ceramic bone substitutes. A magnesium/carbonate substituted apatite would also find application for use in chromatography and for purification, such as the removal of heavy metal ions by adsorption.
The preparation of magnesium/carbonate-substituted hydroxyapatite ceramic materials must be easy and reproducible in order to achieve commercial exploitation. Additionally, the magnesium/carbonate-substituted hydroxyapatite composition must be thermally stable such that it will not decompose to undesirable secondary phases (e.g. tricalcium phosphate or calcium oxide) upon calcining/sintering. Furthermore, during this heat treatment, the magnesium/carbonate-substituted hydroxyapatite must not loose the carbonate ions that have been substituted into hydroxyapatite structure.
Up to the present time, methods which have been reported to prepare magnesium/carbonate-substituted hydroxyapatite compositions have resulted in materials which are not stable on heating and which decompose to undesirable phases such as xcex2-tricalcium phosphate.
e. g. A. Bigi, G. Falini, E. Foresti, M. Gazzano, A. Ripamonti and N. Roveri, xe2x80x9cMagnesium influence on hydroxyapatite crystallisationxe2x80x9d, J. Inorg. Biochem. 49 (1993) 69-78.
R. N. Correia, M. C. F. Magalhaes, P. A. A. P. Marques and A. M. R. Senos, xe2x80x9cWet synthesis and characterization of modified hydroxyapatite powdersxe2x80x9d, J. Mat. Sc. Mater. in Med. 7 (1996) 501-505.
R. Z. LeGeros, R. Kijkowska, C. Bautista and J. P. LeGeros, xe2x80x9cSynergistic effects of magnesium and carbonate on properties of biological and synthesis apatitesxe2x80x9d, Conn. Tiss, Res. 33(1995) 203-209.
JP-A-6245992 discloses the preparation of a hydroxyaptite containing Ca, Mg, P and/or carbonate for repairing defective bones. The method as described therein is not a precipitation method and results in materials that are not single phase after sintering, but are biphasic comprising hydroxyapatite and xcex1- or xcex2-Ca3(PO4)2 or CaO. The resulting product had a (Ca+Mg/P) ratio of between 1.50 and 1.67.
Furthermore, the wet precipitation methods generally use Na2CO3 or (NH4)2CO3as the source of carbonate ions. This causes the problem that the unwanted additional ions Na+ or NH4+ are substituted into the hydroxyapatite structure.
It is due to the problems encountered with the stability of magnesium/carbonate-substituted hydroxyapatite that this material has not been developed commercially.
We have now developed a novel process for the preparation of magnesium- and carbonate-substituted hydroxyapatite which results in a material which is stable on heating and which does not contain sodium or ammonium ions.
Accordingly, the present invention provides a process for the preparation of a single phase magnesium- and carbonate-substituted hydroxyapatite composition, which process comprises the steps of
(i) preparing an aqueous solution containing CO32xe2x88x92 and PO43xe2x88x92 ions in the substantial absence of cations other than H+ ions:
(ii) mixing the solution from step (i) with an aqueous calcium- and magnesium-containing solution or suspension; and
(iii) collecting and drying the precipitate formed in step (ii);
the ratio of (Ca+Mg/P) in the calcium- and magnesium-containing solution or suspension and the phosphorus-containing solution, when mixed together, being maintained at 1.67, or above.
The magnesium- and carbonate-substituted hydroxyapatite produced according to the present invention are believed to be novel and accordingly, in a further aspect the present invention provides a single phase magnesium- and carbonate-substituted hydroxyapatite composition which comprises up to 0.5% by weight of magnesium and up to 1% by weight of carbonate substituted into the hydroxyapatite structure and which does not contain Na+ or NH4 ions, the ratio of (Ca+Mg/P) being greater than 1.67. Preferably, the ratio of (Ca+Mg/P) is 1.68 or above.
In carrying out the process of the present invention the aqueous solution of step (i) may be prepared by bubbling carbon dioxide through water to form carbonic acid, and then adding phosphoric acid, H3PO4, thereto, or by adding carbon dioxide gas to water under high pressure and then adding phosphoric acid thereto. The amount of carbon dioxide absorbed by the solution can be calculated from the pH of the solution prior to the addition of H3PO4. At a pH of about 4.0 the solution will be fully saturated with carbon dioxide. Generally H3PO4 will be added to the solution of carbonic acid in order to provide the PO43 xe2x88x92 ions for reaction.
Alternatively, the aqueous solution of step (i) may be prepared by bubbling carbon dioxide through a solution of H3PO4, or adding carbon dioxide under pressure to a solution of H3PO4, in order to form CO32xe2x88x92 ions in situ. Furthermore, Co2 may be introduced as a solid which carbonates the solution as it vaporises.
The solution from step (i) of the process is mixed in step (ii) with an aqueous calcium- and magnesium-containing solution or suspension. Calcium compounds which may be used include calcium nitrate, Ca(NO3)2, or calcium hydroxide, Ca(OH)2. Magnesium compounds which may be used include magnesium nitrate or magnesium acetate. Preferably the mixing will be carried out by dropwise addition of the solution from step (i) to the calcium- and magnesium-containing solution or suspension. However, bulk mixing of the solution from step (i) and the solution or suspension from step (ii) may be undertaken provided that the combined mixture is vigorously stirred in order to provide the precipitation reaction.
During the mixing in step (ii) of the process carbon dioxide may be bubbled through the mixture.
The ratio of Ca and Mg to P in the calcium- and magnesium-containing solution or suspension and the phosphorus-containing solution, when mixed together, is maintained at 1.67 or above.
Preferably the Ca and Mg/P ratio is maintained at 1.67.
After the addition of the reactants is complete, the pH of the mixture may be adjusted, if desired to pH 10 to 11 by the addition of ammonia. If ammonia is added in this manner then appropriate steps are taken to remove ammonia from the final product.
The dried precipitate from step (iii) of the process may be calcined/sintered in a wet carbon dioxide atmosphere according to the teaching of EP-0625490B. In particular, the dried precipitate may be calcined in carbon dioxide containing from 0.001 to 0.10 of grams of water per litre of gas at a temperature in the range of from 900xc2x0 to 1200xc2x0 C. Preferably the carbon dioxide used as the sintering atmosphere will contain from 0.01 to 0.02 grams of water per litre of gas. The sintering time will generally be up to 24 hours, preferably 10 minutes to 4 hours.
The sintering will generally be carried out at atmospheric pressure, i.e. no imposed pressure, although pressures slightly higher than atmospheric may be produced by the particular configuration of the furnace used.
The magnesium- and carbonate-substituted carbonated hydroxyapatite compositions produced according to the process of the present invention will generally comprise up to 0.5% by weight of magnesium ions and up to 1% by weight of CO32 ions, preferably 1%.
The process of the present invention enables single phase magnesium/carbonate-substituted hydroxyapatite compositions to be prepared which are stable on heating. These materials are very different from the magnesium and magnesium/carbonate-substituted apatites which have previously been reported in the literature.
The single phase magnesium- and carbonate-substituted hydroxyapatite compositions produced according to the process of the present invention are prepared in the substantial absence of cations other than H+ and Ca2+. Accordingly, the compositions do not contain other cations, such as Na+ or NH4+, substituted in their structures, and thus have enhanced bioactivity. The magnesium and carbonate-substituted hydroxyapatite compositions prepared in accordance with the present invention may be used in any of the applications for which hydroxyapatite is used, for example the formation of plasma-sprayed coatings on metallic implants, the formation of porous ceramic bone substitutes, the preparation of composites with polymeric materials such as high density polyethylene, as granules or beads for packing or filling bone defects, as materials for use in chromatography or as materials for use in purification methods such as the removal of heavy metals by adsorption.